455P - Phase I study of LEE011 (CDK4/6 inhibitor) in patients with malignant rhabdoid tumors, neuroblastoma, and cyclin D-CDK4/6 pathway-activated tumors

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Clinical research
Central Nervous System Malignancies
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Birgit Geoerger
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors B. Geoerger1, F. Bourdeaut2, S.G. Dubois3, M. Dewire4, A. Marabelle5, A. Pearson6, S. Modak7, R. Kan8, A. Matano9, S.G. Bhansali10, S. Parasuraman8, S.N. Chi11
  • 1Département De Pédiatrie, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 2Département De Pédiatrie, Institut Curie, Paris/FR
  • 3Pediatric Hematology/oncology, University of California–San Francisco, San Francisco/US
  • 4Uc Department Of Pediatrics, Cincinnati Children's Hospital MC, Cincinnati/US
  • 5Institute For Pediatric Hemato-oncology, Leon Berard Comprehensive Cancer Center, Lyon/FR
  • 6Children And Young People's Unit, Royal Marsden Hospital and the Institute of Cancer Research, London/GB
  • 7Department Of Pediatrics, Memorial Sloan Kettering Cancer Center, New York/US
  • 8Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge/US
  • 9Oncology Translational Medicine, Novartis Pharma AG, Basel/CH
  • 10Clincal Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 11Pediatric Neuro-oncology Program, Dana-Farber Cancer Institute, Boston/US



SMARCB1 mutations are observed in the majority of malignant rhabdoid tumors (MRTs) rendering them dependent on cyclin D1 (CCND1) for genesis and survival. Genetic aberrations in CCND1 and CDK4 are frequent in neuroblastoma cell lines. LEE011 is an orally bioavailable, selective inhibitor of CDK4/6 that has demonstrated tumor growth inhibition in MRT and neuroblastoma preclinical models. In this Phase I study, LEE011 is being investigated in patients (pts) with MRT, neuroblastoma, or other cancers with documented cyclin D–CDK4/6–INK4a–Rb pathway aberrations.


Pts (aged 1–21 years) receive escalating once-daily doses of LEE011 on a 3-weeks-on, 1-week-off schedule. Dose escalation is guided by a Bayesian Logistic Regression Model with overdose control principle and real-time PK. Primary objective: MTD and/or recommended dose for expansion (RDE) determination. Secondary objectives: safety, PK, and efficacy.


As of April 8, 2014, 22 pts (11 MRT [9 primary central nervous system (CNS) and 2 extra-CNS], 10 neuroblastoma, and 1 CDK4-amplified alveolar rhabdomyosarcoma) have received LEE011: 5 at 280 mg/m2; 9 at 350 mg/m2; 8 at 470 mg/m2. The median age was 5 (1–20) years. Two DLTs were reported: 1 Grade (G)3 fatigue at 280 mg/m2; 1 G4 thrombocytopenia at 470 mg/m2. Study drug-related all-grade AEs (N = 20; ≥20%) included neutropenia (75%), leukopenia (65%), anemia (40%), thrombocytopenia (40%), lymphopenia (35%), vomiting (25%), decreased appetite (20%), electrocardiogram QT prolongation (20%), fatigue (20%), and nausea (20%). G3/4 AEs (>10%) included neutropenia (70%), leukopenia (35%), thrombocytopenia (25%), and lymphopenia (15%). Preliminary PK analysis showed that exposure following 280 and 350 mg/m2 is comparable to equivalent doses in adults and slightly higher at 470 mg/m2. LEE011 is rapidly absorbed with Tmax ranging from 1–4 hrs (median: 2–3 hrs) across dose levels. To date, best response obtained is stable disease.


LEE011 demonstrated an acceptable safety profile and dose-dependent PK. Enrollment continues to identify the MTD/RDE and there will be expansion arms for pts with MRT or neuroblastoma at the RDE.


S.G. Dubois: is the site PI for industry sponsored clinical trials (Merck and Novartis). He is also the study chair for a trial funded by Millennium; A. Marabelle: is a member of Advisory Boards for Novartis, BMS, Roche/Genentech, Celgene, Bayer, and Flexus Biotech; S. Modak: has served on an advisory board for Novartis for an unrelated drug; R. Kan: is an employee of and holds shares in Novartis Pharma AG A. Matano: is an employee of Novartis Pharma AG; S.G. Bhansali: is an employee of and holds shares in Novartis Pharmaceuticals Corporation; S. Parasuraman: is an employee of and holds shares in Novartis Pharma AG.All other authors have declared no conflicts of interest.